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Burr, Marian L.; Sparbier, Christina E.; Chan, Kah Lok; Chan, Yih-Chih; Kersbergen, Ariena; Lam, Enid Y.N.; Azidis-Yates, Elizabeth; Vassiliadis, Dane; Bell, Charles C.; Gilan, Omer; Jackson, Susan; Tan, Lavinia; Wong, Stephen Q.; Hollizeck, Sebastian; Michalak, Ewa M.; Siddle, Hannah V.; McCabe, Michael T.; Prinjha, Rab K.; Guerra, Glen R.; Solomon, Benjamin J.; Sandhu, Shahneen; Dawson, Sarah-Jane; Beavis, Paul A.; Tothill, Richard W.; Cullinane, Carleen; Lehner, Paul J.; Sutherland, Kate D.; Dawson, Mark A.
Cancer cell, 10/2019, Letnik: 36, Številka: 4Journal Article
Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion. Display omitted •PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression•Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells•Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity•Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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